Particle formation

ABSTRACT

Spray-coated pharmaceutical powder compositions for transdermal administration using a needleless syringe comprise seed particles coated with a pharmaceutical composition, the said coated seed particles having an average size of about 10 to 100 μm and having an envelope density ranging from about 0.1 to about 25 g/cm 3 .

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of U.S. patent application Ser.No. 09/410,692, filed Oct. 1, 1999, and is related to U.S. provisionalapplication serial No. 60/102,726, filed Oct. 1, 1998, from whichapplications priority is claimed pursuant to 35 U.S.C. §§119(e)(1) and120 and which applications are incorporated herein by reference in theirentirety.

TECHNICAL FIELD

[0002] The invention relates to a method for producing powderedpharmaceutical compositions. More specifically, the invention relates toa method for forming dense, substantially solid particles frompharmaceutical compositions, where the particulate compositions areparticularly suitable for transdermal particle delivery from aneedleless syringe system.

BACKGROUND

[0003] The ability to deliver pharmaceuticals through skin surfaces(transdermal delivery) provides many advantages over oral or parenteraldelivery techniques. In particular, transdermal delivery provides asafe, convenient and noninvasive alternative to traditional drugadministration systems, conveniently avoiding the major problemsassociated with oral delivery (e.g., variable rates of absorption andmetabolism, gastrointestinal irritation and/or bitter or unpleasant drugtastes) or parenteral delivery (e.g., needle pain, the risk ofintroducing infection to treated individuals, the risk of contaminationor infection of health care workers caused by accidental needle-sticksand the disposal of used needles).

[0004] However, despite its clear advantages, transdermal deliverypresents a number of its own inherent logistical problems. The passivedelivery of drugs through intact skin necessarily entails the transportof molecules through a number of structurally differenttissues,including the stratum corneum, the viable epidermis, thepapillary dermis, and the capillary walls in order for the drug to gainentry into the blood or lymph system. Transdermal delivery systems musttherefore be able to overcome the various resistances presented by eachtype of tissue. In light of the above, a number of alternatives topassive transdermal delivery have been developed. These alternativesinclude the use of skin penetration enhancing agents, or “permeationenhancers,” to increase skin permeability, as well as non-chemical modessuch as the use of iontophoresis, electroporation or ultrasound.However, these alternative techniques often give rise to their ownunique side effects, such as skin irritation or sensitization. Thus, thespectrum of pharmaceuticals that can be safely and effectivelyadministered using traditional transdermal delivery methods has remainedlimited.

[0005] More recently, a novel transdermal drug delivery system thatentails the use of a needleless syringe to fire powders (i.e., soliddrug-containing particles) in controlled doses into and through intactskin has been described. In particular, commonly owned U.S. Pat. No.5,630,796 to Bellhouse et al. describes a needleless syringe thatdelivers pharmaceutical particles entrained in a supersonic gas flow.The needleless syringe is used for transdermal delivery of powdered drugcompounds and compositions, for delivery of genetic material into livingcells (e.g., gene therapy) and for the delivery of biopharmaceuticals toskin, muscle, blood or lymph. The needleless syringe can also be used inconjunction with surgery to deliver drugs and biologics to organsurfaces, solid tumors and/or to surgical cavities (e.g., tumor beds orcavities after tumor resection). In theory, practically anypharmaceutical agent that can be prepared in a substantially solid,particulate form can be safely and easily delivered using such devices.

[0006] One particular needleless syringe generally comprises an elongatetubular nozzle having a rupturable membrane initially closing thepassage through the nozzle and arranged substantially adjacent to theupstream end of the nozzle. Particles of a therapeutic agent to bedelivered are disposed adjacent to the rupturable membrane and aredelivered using an energizing means which applies a gaseous pressure tothe upstream side of the membrane sufficient to burst the membrane andproduce a supersonic gas flow (containing the pharmaceutical particles)through the nozzle for delivery from the downstream end thereof. Theparticles can thus be delivered from the needleless syringe at deliveryvelocities of between Mach 1 and Mach 8 which are readily obtainableupon the bursting of the rupturable membrane.

[0007] Another needleless syringe configuration generally includes thesame elements as described above, except that instead of having thepharmaceutical particles entrained within a supersonic gas flow, thedownstream end of the nozzle is provided with a bistable diaphragm whichis moveable between a resting “inverted” position (in which thediaphragm presents a concavity on the downstream face to contain thepharmaceutical particles) and an active “everted” position (in which thediaphragm is outwardly convex on the downstream face as a result of asupersonic shockwave having been applied to the upstream face of thediaphragm). In this manner, the pharmaceutical particles containedwithin the concavity of the diaphragm are expelled at a supersonicinitial velocity from the device for transdermal delivery thereof to atargeted skin or mucosal surface.

[0008] Transdermal delivery using either of the above-describedneedleless syringe configurations is carried out with particles havingan approximate size that generally ranges between 0.1 and 250 μm. Fordrug delivery, an optimal particle size is usually at least about 10 to15 μm (the size of a typical cell). For gene delivery, an optimalparticle size is generally substantially smaller than 10 μm. Particleslarger than about 250 μm can also be delivered from the device, with theupper limitation being the point at which the size of the particleswould cause untoward damage to the skin cells. The actual distance whichthe delivered particles will penetrate depends upon particle size (e.g.,the nominal particle diameter assuming a roughly spherical particlegeometry), particle density, the initial velocity at which the particleimpacts the skin surface, and the density and kinematic viscosity of theskin. In this regard, optimal particle densities for use in needlelessinjection generally range between about 0.1 and 25 g/cm³, preferablybetween about 0.8 and 1.5 g/cm³, and injection velocities generallyrange between about 100 and 3,000 m/sec.

SUMMARY OF THE INVENTION

[0009] It is a primary object of the invention to provide a spray-coatedpowder composition for administration from a needleless syringe. It isalso a primary object of the invention to provide suitable spray-coatingmethods for producing such powder compositions.

[0010] In one aspect of the invention, a spray-coated powder compositionfor administration from a needleless syringe is provided. The powdercomposition is formed from seed particles that are coated with anaqueous pharmaceutical composition. More especially, the spray-coatedpowder composition comprises seed particles coated with a pharmaceuticalcomposition, the said coated seed particles having an average size ofabout 10 to 100 μm and having an envelope density ranging from about 0.1to about 25 g/cm³.

[0011] The coated seed particles can have an average size of about 20 to70 μm. Preferably, they have an envelope density ranging from about 0.8to about 1.5 g/cm³. The coated seed particles typically have asubstantially spherical aerodynamic shape and/or a substantiallyuniform, nonporous surface. The powders may also be characterized inthat the coated seed particles have a pharmaceutical composition loadingof about 1 to 50 wt %. The spray-coated powder compositions can contain,as the active pharmaceutical agent, any small molecule drug substance,organic or inorganic chemical, vaccine, or peptide (polypeptide and/orprotein) of interest.

[0012] In another aspect of the invention, a method for preparing thespray-coated powder composition is provided. The method comprisesspray-coating an aqueous pharmaceutical composition onto seed particlesunder conditions sufficient to provide coated particles having anaverage size of about 10 to 100 μm and an envelope density ranging fromabout 0.1 to about 25 g/cm³. In one particular embodiment, the methodentails the steps of: (a) suspending the seed particles in a reactionchamber using a hot air flow; (b) atomizing an aqueous pharmaceuticalcomposition into a fine spray and introducing the spray into thereaction chamber; (c) allowing the spray to spread over the surface ofthe suspended seed particles to coat them with a thin film; and then (d)drying the coated seed particles. If desired, the aqueous pharmaceuticalcomposition can be sprayed into the reaction chamber in a direction thatis transverse to the direction of the hot air flow.

[0013] It is an advantage of the invention that free-flowing powdercompositions can be produced having well defined particle size, densityand mechanical properties which collectively are suitable fortransdermal delivery from a needleless syringe. Further advantages ofthe methods of the invention include flexible pharmaceutical loading (upto about 50 wt %), overall process efficiency (no need forpost-formulation fractionation, classification or sieving operations),and the methods are readily scalable. The invention further provides:

[0014] a dosage receptacle for a needleless syringe, said receptaclecontaining a therapeutically effective amount of a spray-coated powdercomposition of the invention; and

[0015] a needleless syringe which is loaded with such a powdercomposition. These and other objects, aspects, embodiments andadvantages of the present invention will readily occur to those ofordinary skill in the art in view of the disclosure herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified compositions or process parameters as such may, of course,vary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments of the inventiononly, and is not intended to be limiting.

[0017] All publications, patents and patent applications cited herein,whether supra or infra, are hereby incorporated by reference in theirentirety.

[0018] It must be noted that, as used in this specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the content clearly dictates otherwise. Thus, forexample, reference to “a particle” includes a mixture of two or moresuch particles, reference to “an excipient” includes mixtures of two ormore such excipients, and the like.

[0019] A. Definitions

[0020] Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although a number ofmethods and materials similar or equivalent to those described hereincan be used in the practice of the present invention, the preferredmaterials and methods are described herein.

[0021] In describing the present invention, the following terms will beemployed, and are intended to be defined as indicated below.

[0022] By “transdermal delivery,” applicant intends to include bothtransdermal (“percutaneous”) and transmucosal routes of administration,i.e., delivery by passage of a drug or pharmaceutical agent through theskin or mucosal tissue. See, e.g., Transdermal Drug Delivery:Developmental Issues and Research Initiatives, Hadgraft and Guy (eds.),Marcel Dekker, Inc., (1989); Controlled Drug Delivery: Fundamentals andApplications, Robinson and Lee (eds.), Marcel Dekker Inc., (1987); andTransdermal Delivery of Drugs, Vols. 1-3, Kydonieus and Berner (eds.),CRC Press, (1987).

[0023] As used herein, the term “pharmaceutical” or “pharmaceuticalagent” intends any compound or composition of matter which, whenadministered to an organism (human or animal) induces a desiredpharmacologic and/or physiologic effect by local and/or systemic action.The term therefore encompasses those compounds or chemicalstraditionally regarded as drugs, as well as biopharmaceuticals includingmolecules such as peptides, hormones, nucleic acids, gene constructs andthe like. More particularly, the term “pharmaceutical” or“pharmaceutical agent” includes compounds or compositions for use in allof the major therapeutic areas including, but not limited to,anti-infectives such as antibiotics and antiviral agents; analgesics andanalgesic combinations; local and general anesthetics; anorexics;antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants;antihistamines; anti-inflammatory agents; antinauseants;antineoplastics; antipruritics; antipsychotics; antipyretics;antispasmodics; cardiovascular preparations (including calcium channelblockers, beta-blockers, beta-agonists and antiarrythmics);antihypertensives; diuretics; vasodilators; central nervous systemstimulants; cough and cold preparations; decongestants; diagnostics;hormones; bone growth stimulants and bone resorption inhibitors;immunosuppressives; muscle relaxants; psychostimulants; sedatives;tranquilizers; therapeutic proteins (e.g., antigens, antibodies, growthfactors, cytokines, interleukins, lymphokines, interferons, enzymes,etc.), peptides and fragments thereof (whether naturally occurring,chemically synthesized or recombinantly produced); and nucleic acidmolecules (polymeric forms of two or more nucleotides, eitherribonucleotides (RNA) or deoxyribonucleotides (DNA) including bothdouble- and single-stranded molecules, gene constructs, expressionvectors, antisense molecules and the like).

[0024] The above pharmaceuticals or pharmaceutical agents, alone or incombination with other agents, are typically prepared as pharmaceuticalcompositions which can contain one or more added materials such ascarriers, vehicles, and/or excipients. “Carriers,” “vehicles” and“excipients” generally refer to substantially inert materials which arenontoxic and do not interact with other components of the composition ina deleterious manner. These materials can be used to increase the amountof solids in particulate pharmaceutical compositions. Examples ofsuitable carriers include water, silicone, gelatin, waxes, and likematerials. Examples of normally employed “excipients,” includepharmaceutical grades of carbohydrates including monosaccharides,disaccharides, cyclodextrans, and polysaccharides (e.g., dextrose,sucrose, lactose, trehalose, raffinose, mannitol, sorbitol, inositol,dextrans, and maltodextrans); starch; cellulose; salts (e.g. sodium orcalcium phosphates, calcium sulfate, magnesium sulfate); citric acid;tartaric acid; glycine; high molecular weight polyethylene glycols(PEG); Pluronics; surfactants; and combinations thereof. Generally, whencarriers and/or excipients are used, they are used in amounts rangingfrom about 0.1 to 99 wt % of the pharmaceutical composition.

[0025] The terms “individual” and “subject” are used interchangeablyherein to refer to any member of the subphylum cordata, including,without limitation, humans and other primates, including non-humanprimates such as chimpanzees and other apes and monkey species; farmanimals such as cattle, sheep, pigs, goats and horses; domestic mammalssuch as dogs and cats; laboratory animals including rodents such asmice, rats and guinea pigs; birds, including domestic, wild and gamebirds such as chickens, turkeys and other gallinaceous birds, ducks,geese, and the like. The terms do not denote a particular age. Thus,both adult and newborn individuals are intended to be covered. Themethods described herein are intended for use in any of the abovevertebrate species, since the immune systems of all of these vertebratesoperate similarly.

[0026] The term “powder,” as used herein, refers to a composition thatconsists of substantially solid particles that can be deliveredtransdermally using a needleless syringe device. The particles that makeup the powder can be characterized on the basis of a number ofparameters including, but not limited to, the average particle size, theaverage particle density, particle morphology (e.g., particleaerodynamic shape and particle surface characteristics), and particlepenetration energy (P.E.).

[0027] The average particle size of the powders produced according tothe present invention can vary widely and is generally between about 10and 100 μm, more typically between about 20 and 70 μm. The averageparticle size of the powder can be measured as a mass mean aerodynamicdiameter (MMAD) using conventional techniques such as microscopictechniques (where particles are sized directly and individually ratherthan grouped statistically), absorption of gasses, permeability or timeof flight. If desired, automatic particle-size counters can be used(e.g., Aerosizer Counter, Coulter Counter, HIAC Counter, or GelmanAutomatic Particle Counter) to ascertain the average particle size.

[0028] Actual particle density, or “absolute density,” can be readilyascertained using known quantification techniques such as heliumpycnometry and the like. Alternatively, envelope (“tap”) densitymeasurements can be used to assess the density of a particulatepharmaceutical composition produced according to the methods of theinvention. Envelope density information is particularly useful incharacterizing the density of objects of irregular size and shape.Envelope density is the mass of an object divided by its volume, wherethe volume includes that of its pores and small cavities but excludesinterstitial space. A number of methods of determining envelope densityare known in the art, including wax immersion, mercury displacement,water absorption and apparent specific gravity techniques. A number ofsuitable devices are also available for determining envelope density,for example, the Geopyc™ Model 1360, available from the MicromeriticsInstrument Corp. The difference between the absolute density andenvelope density of a sample pharmaceutical composition providesinformation about the sample's percentage total porosity and specificpore volume.

[0029] Particle morphology, particularly the aerodynamic shape of aparticle, can be readily assessed using standard light microscopy. It ispreferred that the particles which make up the instant powders have asubstantially spherical or at least substantially elliptical aerodynamicshape. It is also preferred that the particles have an axis ratio of 3or less to avoid the presence of rod- or needle-shaped particles. Thesesame microscopic techniques can also be used to assess the particlesurface characteristics, e.g., the amount and extent of surface voids ordegree of porosity.

[0030] Particle penetration energies can be ascertained using a numberof conventional techniques, for example a metallized film P.E. test.

[0031] B. General Methods

[0032] In one embodiment, a powdered pharmaceutical composition isprovided, wherein the powder composition (which is comprised ofparticles) is produced using a spray-coating technique. The powders aresuitable for transdermal administration from a needleless syringedelivery system, and as such, the particles which make up the powderedcomposition must have sufficient physical strength to withstand suddenacceleration to several times the speed of sound and the impact with,and passage through, the skin and tissue. The particles are formed byspray-coating an aqueous pharmaceutical composition onto suitable seedparticles. The particles can be delivered from a needleless syringesystem such as those described in commonly owned InternationalPublication Nos. WO 94/24263, WO 96/04947, WO 96/12513, and WO 96/20022,all of which are incorporated herein by reference.

[0033] The aqueous pharmaceutical compositions can contain, as theactive pharmaceutical agent, any small molecule drug substance, organicor inorganic chemical, vaccine, or peptide (polypeptide and/or protein)of interest. In particular embodiments, the pharmaceutical agent is abiopharmaceutical preparation of a peptide, polypeptide, protein or anyother such biological molecule. Exemplary peptide and proteinformulations include, without limitation, insulin; calcitonin;octreotide; endorphin; liprecin; pituitary hormones (e.g., human growthhormone and recombinant human growth hormone (hGH and rhGH), HMG,desmopressin acetate, etc); follicle luteoids; growth factors (such asgrowth factor releasing factor (GFRF), somatostatin, somatotropin andplatelet-derived growth factor); asparaginase; chorionic gonadotropin;corticotropin (ACTH); erythropoietin (EPO); epoprostenol (plateletaggregation inhibitor); glucagon; interferons; interleukins; menotropins(urofollitropin, which contains follicle-stimulating hormone (FSH); andluteinizing hormone (LH)); oxytocin; streptokinase; tissue plasminogenactivator (TPA); urokinase; vasopressin; desmopressin; ACTH analogues;angiotensin II antagonists; antidiuretic hormone agonists; bradykininantagonists; CD4 molecules; antibody molecules and antibody fragments(e.g., Fab, Fab₂, Fv and sFv molecules); IGF-1; neurotrophic factors;colony stimulating factors; parathyroid hormone and agonists;parathyroid hormone antagonists; prostaglandin antagonists; protein C;protein S; renin inhibitors; thrombolytics; tumor necrosis factor (TNF);vaccines (particularly peptide vaccines including subunit and syntheticpeptide preparations); vasopressin antagonists analogues; and α-1antitrypsin. Additionally, nucleic acid preparation, such as vectors orgene constructs for use in subsequent gene delivery, can be used.

[0034] The pharmaceutical agent is typically prepared as an aqueouspharmaceutical composition using a suitable aqueous carrier, along withsuitable excipients, protectants, solvents, salts, surfactants,buffering agents and the like. Suitable excipients can includefree-flowing particulate solids that do not thicken or polymerize uponcontact with water, which are innocuous when administered to anindividual, and do not significantly interact with the pharmaceuticalagent in a manner that alters its pharmaceutical activity. In general,excipients which are sticky, or have high hygroscopicity are avoidedparticularly for powder formulations where the pharmaceutical is loadedonto the seed particle at a high concentration (e.g., >10 wt %).Examples of normally employed excipients include, but are not limitedto, pharmaceutical grades of dextrose, sucrose, lactose, trehalose,mannitol, sorbitol, inositol, dextran, starch, cellulose, sodium orcalcium phosphates, calcium carbonate, calcium sulfate, sodium citrate,citric acid, tartaric acid, glycine, high molecular weight polyethyleneglycols (PEG), and combinations thereof. Suitable solvents include, butare not limited to, methylene chloride, acetone, methanol, ethanol,isopropanol and water. Generally pharmaceutically acceptable saltshaving molarities ranging from about 1 mM to 2M can be used.Pharmaceutically acceptable salts include, for example, mineral acidsalts such as hydrochlorides, hydrobromides, phosphates, sulfates, andthe like; and the salts of organic acids such as acetates, propionates,malonates, benzoates, and the like. A thorough discussion ofpharmaceutically acceptable excipients, vehicles and auxiliarysubstances is available in REMINGTON'S PHARMACEUTICAL SCIENCES (MackPub. Co., N.J. 1991), incorporated herein by reference.

[0035] The seed particles can be comprised of any parenterallyacceptable powder (e.g., crystalline or amorphous), are selected to havegood flowability (i.e., are fluidizable), and are sufficiently dense forefficient use with needleless transdermal delivery systems. Crystallineparticles are generally preferred due to their inherently high particledensity and overall penetration energy. Seed particles having an overallspherical or at least elliptical shape are preferred. Particlesgenerally are selected to have an axis ratio of 3 or less, for example 2or less or 1.5 or less, in order to avoid rod- or needle-shapedparticles which are difficult to reprocess and are generally lessflowable.

[0036] Suitable seed particles can be comprised of any pharmaceuticallyacceptable carbohydrate (e.g., sugars such as lactose, mannitol,trehalose, etc.), polysaccharide, starch, biodegradable polymer (e.g.PLGA, a copolymer of L-lactic acid and glycolic acid), or the like. Theseed particles can have an average size of about 5 to 100 μm, forexample about 10 to 95 μm or about 20 to 70 μm. Seed particlepreparations having a substantially homogenous average particle size canbe readily obtaining using standard sieving or other particleclassification methodologies.

[0037] The spray-coated powders can be formed using any standardspray-coating processing apparatus. In this regard, batch-type fluid-bedprocessors have long been used to perform drying, granulation, andcoating operations in the pharmaceutical industry for preparing soliddosage forms. Olsen, K. W. (1989) “Batch fluid-bed processing equipment:A design overview,” Part I., Pharm. Technol. 13:34-46, Olsen, K. W.(1989) “Batch fluid-bed processing equipment: A design overview,” PartII., Pharm. Technol. 13:39-50. With the advent of the Würster spraycoater, seed particles as small as 50 μm in size can, at least intheory, be coated. Iyer et al. (1993) Drug Devel. Ind. Pharm.19:981-989. However, to date, the spray coating of seed particles havingan average size of 100 μm or less has been limited, particularly forprotein or peptide pharmaceuticals. Maa et al. (1996) Intl. J.Pharmaceutics 144:47-59.

[0038] Spray coating processors that can fluidize seed particles of 10μm or larger, for example 20 μm and larger, and which can atomize a finespray (droplet size of 30 μm or less, preferably 10 μm or less) arepreferred. Suitable processors include any commercially availableWürster spray coater, or Würster HS spray coater (available from GlattAir Techniques, Inc.). For fluid-bed processing, the spray coatingprocessor can utilize any suitable spraying method which is selected inconsideration of the desired characteristics for the finished product.These spraying methods (e.g., top, bottom or tangential (rotary coater))are generally known to those skilled in the art.

[0039] The liquid delivery system for the spray coat processor typicallyutilizes a binary nozzle, where the aqueous pharmaceutical compositionis supplied at a relatively low pressure through an orifice and isatomized by air. Pneumatic nozzles can be used to produce smallerdroplets. The atomization conditions, including atomization gas flowrate, atomization gas pressure, liquid flow rate, etc., can becontrolled to produce droplets from the pharmaceutical compositionhaving an average diameter of about 30 μm or less, with droplets havingan average size of 10 μm or less being preferred. Typically, theatomizing air pressure, liquid flow rate and the fluidizing airtemperature and volume are the most significant process variables andhave the greatest effect over the particle characteristics of theresultant coated particles. Drying temperature conditions of about50-150° C. inlet temperature and about 30-100° C. outlet temperature arepreferred. The thickness of the pharmaceutical coat can be controlled bythe drying time, and the present methods can provide spray-coatedpowders formed from seed particles loaded with from about 1 to 50 wt %(e.g., about 0.5 to 15 wt % of active pharmaceutical agent incompositions containing both active pharmaceutical agent and carrier),preferably >10 wt % of the aqueous pharmaceutical composition.

[0040] If desired, a secondary coating process can be used to providefurther structural integrity in the coated particles, for example, wherethe spray-coated powder particles are coated with a standard sugarexcipient using the same sort of spray-coating procedure as describedherein above. In some cases, it may be desirable to coat thespray-coated powder particles with the same sugar used as the seed(e.g., mannitol, lactose, trehalose, or the like). Other secondarycoating materials include, but are not limited to, pharmaceutical gradesof carbohydrates including monosaccharides, disaccharides,cyclodextrans, and polysaccharides (e.g., dextrose, sucrose, raffinose,mannose, sorbitol, inositol, dextrans, and maltodextrans); starch;cellulose; salts (e.g. sodium or calcium phosphates, calcium sulfate,magnesium sulfate); citric acid; tartaric acid; glycine; high molecularweight polyethylene glycols (PEG); Pluronics; surfactants; andcombinations thereof. The secondary coating material can also be used tooptimize the particles for delivery to mucosal target surfaces (e.g., bycoating the spray-coated powder particles with a lipid), or to alter orretard solubility characteristics of the particles after delivery intoan aqueous environment (e.g., by applying a secondary coating containinga salt, starch, dextran, or the like).

[0041] The spray-coating methods of the present invention can be used toproduce powders that are suitable for transdermal delivery from aneedleless syringe delivery device. Typical powders are characterized inthat the individual particles have an average size in the range of about20 to 70 μm, an envelope density ranging from about 0.1 to about 25g/cm³, preferably ranging from about 0.8 to about 1.5 g/cm³, and have asubstantially spherical aerodynamic shape with a substantially uniform,nonporous surface.

[0042] The particles which make up the spray-coated powders of thepresent invention will also have a particle penetration energy suitablefor transdermal delivery from a needleless syringe device. Suchpenetration energies can conveniently be assessed using a metallizedfilm P.E. measuring procedure as follows. A metallized film material(e.g., a 125 μm polyester film having a 350 Å layer of aluminumdeposited on a single side) is used as a substrate into which the powderis fired from a needleless syringe (e.g., the needleless syringedescribed in U.S. Pat. No. 5,630,796 to Bellhouse et al.) at an initialvelocity of about 100 to 3000 m/sec. The metallized film is placed, withthe metal coated side facing upwards, on a suitable surface. Aneedleless syringe loaded with a spray-coated powder produced accordingto the methods of the invention is placed with its spacer contacting thefilm, and then fired. Residual powder is removed from the metallizedfilm surface using a suitable solvent. Penetration energy is thenassessed using a BioRad Model GS-700 imaging densitometer to scan themetallized film, and a personal computer with a SCSI interface andloaded with MultiAnalyst software (BioRad) and Matlab software (Release5.1, The MathWorks, Inc.) is used to assess the densitometer reading. Aprogram is used to process the densitometer scans made using either thetransmittance or reflectance method of the densitometer. The penetrationenergy of the spray-coated powders should be equivalent to, or betterthan that of reprocessed mannitol particles of the same size (mannitolparticles that are freeze-dried, compressed, ground and sieved accordingto the methods of commonly owned International Publication No. WO97/48485, incorporated herein by reference).

[0043] Once produced, the spray-coated powders of the present inventioncan be packaged in individual unit dosages. As used herein, a “unitdosage” intends a dosage receptacle containing a therapeuticallyeffective amount of a spray-coated pharmaceutical produced according tothe methods of the present invention. The dosage receptacle is generallyone which fits within a needleless syringe device to allow fortransdermal delivery from the device. Such receptacles can be capsules,foil pouches, sachets, cassettes, or the like.

[0044] C. Experimental

[0045] Below are examples of specific embodiments for carrying out themethods of the present invention. The examples are offered forillustrative purposes only, and are not intended to limit the scope ofthe present invention in any way.

[0046] Efforts have been made to ensure accuracy with respect to numbersused (e.g., amounts, temperatures, etc.), but some experimental errorand deviation should, of course, be allowed for.

EXAMPLE 1

[0047] The following spray-coated powder formulations are made using themethods of the present invention.

[0048] Formulation 1:

[0049] Seed particles: 500 grams of lactose (Pharmatose, 100M & 200M,Crompton & Knowle), sieved to provide an average particle size of 20-75μm by jet sieve.

[0050] Aqueous pharmaceutical composition: Lysozyme (50%) and trehalose(50%) at a total solid concentration of 20%.

[0051] Spray coater: GPCG-1 (Glatt Air), operated at the followingcoating conditions: air inlet temperature =85° C., air outlettemperature =42° C., liquid feed =15 mL/min, air velocity in the bed=3.5 m/sec., coating loading 10% of lysozyme, and a coating time =35min.

[0052] Formulation 2:

[0053] Seed particles: 300 grams of lactose (Pharmatose, 100M & 200M,Crompton & Knowle), sieved to provide an average particle size of 20-75μm by jet sieve.

[0054] Aqueous pharmaceutical composition: s-Calcitonin (20%), mannitol(30%), and trehalose (50%) at a total solid concentration of 10%.

[0055] Spray coater: Precision coater (MP-1, Niro), operated at thefollowing coating conditions: air inlet temperature =68° C., air outlettemperature =34° C., liquid feed =12 mL/min, air velocity in the bed=3.5 m/sec., coating loading 5% of s-Calcitonin, and a coating time =63min.

[0056] Formulation 3:

[0057] Seed particles: 300 grams of mannitol (Merck), sieved to providean average particle size of 20-75 μm by jet sieve.

[0058] Aqueous pharmaceutical composition: recombinant human growthhormone (rhGH) (50%), mannitol (20%), glycine (10%), and trehalose (20%)at a total solid concentration of 10%.

[0059] Spray coater: Precision coater (MP-1, Niro), operated at thefollowing coating conditions: air inlet temperature =75° C., air outlettemperature =40° C., liquid feed =13 mL/min, air velocity in the bed=3.5 m/sec., coating loading 5% of rhGH, and a coating time =24 min.

[0060] Formulation 4:

[0061] Seed particles: 500 grams of mannitol (Merck), sieved to providean average particle size of 20-75 μm by jet sieve.

[0062] Aqueous pharmaceutical composition: Bovine serum albumin (BSA)(100%) at a total solid concentration of 10%.

[0063] Spray coater: GPCG-1 (Glatt Air), operated at the followingcoating conditions: air inlet temperature =85° C., air outlettemperature =42° C., liquid feed =15 m/min, air velocity in the bed =3.5m/sec., coating loading 15% of BSA, and a coating time =50 min.

[0064] Formulation 5:

[0065] Seed particles: 300 grams of lactose (Pharmatose, 100M & 200M,Crompton & Knowle), sieved to provide an average particle size of 20-75μm by jet sieve.

[0066] Aqueous pharmaceutical composition: Diphtheria toxoids vaccine(DPT) (2%), mannitol (30%), glycine (8%), and trehalose (60%) at a totalsolid concentration of 10%.

[0067] Spray coater: Precision coater (MP-1, Niro), operated at thefollowing coating conditions: air inlet temperature =75° C., air outlettemperature =40° C., liquid feed =13 mL/min, air velocity in the bed=3.5 m/sec., coating loading 0.5% of DPT, and a coating time =58 min.

[0068] The spray-coated powder formulation of each Example is suitablefor transdermal administration from a needleless syringe and ischaracterized in that the individual spraycoated particles have anaverage size in the range of about 20 to 70 μm, an envelope densityranging from about 0.1 to about 25 g/cm³, preferably ranging from about0.8 to about 1.5 g/cm³, and have a substantially spherical aerodynamicshape with a substantially uniform, nonporous surface.

[0069] Accordingly, novel spray-coated powder compositions, and methodsfor producing these compositions have been described. Although preferredembodiments of the subject invention have been described in some detail,it is understood that obvious variations can be made without departingfrom the spirit and the scope of the invention as defined by theappended claims.

What is claimed is:
 1. A spray-coated powder composition foradministration from a needleless syringe, said powder compositioncomprising seed particles coated with a pharmaceutical composition, thesaid coated seed particles having an average size of about 10 to 100 μmand having an envelope density ranging from about 0.1 to about 25 g/cm³.2. The powder composition of claim 1, wherein said seed particles arecrystalline particles.
 3. The powder composition of claim 1, wherein theseed particles have an axis ratio of 3 or less.
 4. The powdercomposition of claim 1, wherein the seed particles are selected from thegroup consisting of lactose, mannitol, trehalose, polysaccharides,starches, and biodegradable polymers.
 5. The powder composition of claim1, wherein said coated seed particles have an average size of about 20to 70 μm.
 6. The powder composition of claim 1, wherein said coated seedparticles have an envelope density ranging from about 0.8 to about 1.5g/cm³.
 7. The powder composition of claim 1, wherein said coated seedparticles have a substantially spherical aerodynamic shape.
 8. Thepowder composition of claim 1, wherein said coated seed particles have asubstantially uniform, nonporous surface.
 9. The powder composition ofclaim 1, wherein said coated seed particles have a pharmaceuticalcomposition loading of about 1 to 50 wt %.
 10. A method for preparing aspray-coated powder for administration from a needleless syringe, saidmethod comprising spray-coating an aqueous pharmaceutical compositiononto seed particles under conditions sufficient to provide coatedparticles having an average size of about 10 to 100 μm and an envelopedensity ranging from about 0.1 to about 25 g/cm³.
 11. The method ofclaim 10 comprising the steps of: (a) suspending the seed particles in areaction chamber using a heated air flow; (b) atomizing an aqueouspharmaceutical composition into a spray and introducing said spray intothe reaction chamber; (c) allowing the spray to spread over the surfaceof said suspended seed particles to coat said seed particles with afilm; and (d) drying the coated seed particles.
 12. The method of claim11, wherein the aqueous pharmaceutical composition is sprayed into thereaction chamber in a direction that is transverse to the direction ofthe hot air flow.
 13. A dosage receptacle for a needleless syringe, saidreceptacle containing a therapeutically effective amount of aspray-coated powder composition as claimed in claim
 1. 14. Thereceptacle of claim 13, which is selected from the group consisting ofcapsules, foil pouches, sachets and cassettes.
 15. A needleless syringewhich is loaded with a spray-coated powder composition as claimed inclaim 1.